Inhalation provides an effective means for treating a variety of bronchial constriction diseases, such as bronchial asthma, emphysema, bronchitis, and bronchiectasis. An obvious advantage of inhalation in treating bronchial constriction is the ability to deliver the drug directly to the site of drug action. A related advantage is the rapid onset of the therapeutic effect, compared with other routes of administration, such as intramuscular and oral routes. For drugs which are susceptible to breakdown in the gastrointestinal tract, or which otherwise cannot be administered orally, inhalation may be preferred for a variety of reasons over intravenous or intramuscular injection.
Bronchial constriction conditions or diseases are treated with a bronchodilator drug, such as albuterol, epinephrine, isoetharine, isoproteranol, metaproteranol, terbutaline, and salbutamol, which have strong or moderate .beta..sub.2 -adrenoreceptor agonist activity (1), in general, these compounds are uncharged, water-soluble, and relatively small molecules. An aqueous solution of a .beta..sub.2 -agonist drug may be administered in aerosolized form from a pneumatic or ultrasonic nebulizer. Alternatively, the drug can be suspended in micronized form in a fluorocarbon propellant solvent, and delivered in metered dose from a pressurized cannister. Following aerosolization, most of the propellant solvent is lost through flash evaporation and replaced by moisture in the respiratory tract, leading to the deposition of hydrated micronized particles.
Both types of inhalation systems mentioned above are based on delivery of the drug in a free form to sites in the respiratory tract. As such, the drug is rapidly utilized and also in the case of pulmonary deposition, rapidly absorbed into the bloodstream. Because of the rapid drug uptake and utilization, it is generally necessary to administer the drug at frequent intervals to maintain a desired therapeutic dose level at the site of action. Rapid uptake into the bloodstream also limits the amount of drug that can be administered safely with each administration. .beta.-adrenergic agonists generally produce some degree of tachycardia and dizziness, and even at relatively low dose levels, these stimulatory effects are unpleasant to the patient. An additional problem associated with administration of micronized particles is the irritation that these particles may produce in the respiratory tract.
A variety of methods and apparatus which are designed to produce liposome-based aerosols, for drug delivery by inhalation, have been proposed heretofore. UK patent application GB 2,145,107A describes an aerosol device which brings aqueous and organic-solvent phase solutions together under pressure, and passes the mixture through a nozzle to form aerosolized liposomes. EPO patent application 0,158,441 discloses liposome formation, in aerosol form, from a water/lipid/ethanol mixture. In PCT application WO 86/01714, it is proposed to spray lipid droplets in a volatile liquid carrier, with liposome formation occurring upon contact of the droplets with a moist aqueous surface. UK patent application GB 2,170,815 describes a system in which an aqueous solution is emulsified in a lipid-containing propellant solvent, then sprayed through an atomizing nozzle to form lipid-coated droplets which can form liposomes upon contact With a moist surface. All of these approaches are characterized by "in situ" liposome formation, and as such, the concentration and size of the liposomes formed, and the percentage of drug entrapment in the liposomes will vary from one dose delivery to another, depending upon temperature, extent of solvent mixing, and the total and relative amounts of solvent components present in the system. Thus each of these systems would be difficult to adapt for metered dose delivery, where a reproducible amount of liposome-encapsulated drug is needed.
Further, although the above disclosures indicate that a variety of drugs, including bronchodilators, may be delivered in liposomal form, none of the references demonstrate how or whether liposome drug delivery effects the pharmacokinetic action of a liposome-entrapped drug in the respiratory tract. In particular, it is not known from these earlier references how liposomes behave in the respiratory-tract environment, how .beta..sub.2 -agonist activity would be effected by the presence of liposomal lipids, and whether liposomes can significantly modulate drug release and side effects observed with .beta..sub.2 -agonist, particularly at low drug dosage.